HGFプロモーター遺伝子変異によるEGFRチロシンキナーゼ阻害薬の効果予測

• Project/Area Number: 23701106
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Clinical oncology
• Research Institution: Kinki University
• Principal Investigator: 荒尾 徳三 近畿大学, 医学部, 講師 (20441074)
• Project Period (FY): 2011 – 2012
• Project Status: Discontinued (Fiscal Year 2011)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2013: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2012: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2011: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: HGF / 肺がん / 遺伝子変異 / SNP / プロモーター

Research Abstract

本研究ではHGF発現に関与するプロモーター領域のA繰り返し配列数(polyA)とHGF発現の関連を検討した。固形がん細胞73細胞株を対象にpolyA領域の変異を検討したところ、Short polyA(<25bp)の細胞株が7株、正常型のpolyAの細胞株は66株であった。73細胞株のHGFのmRNA発現をrealtime RT-PCRで解析し、HGFのmRNA高値の細胞株では29%(2株/7株)がShortpolyAで、HGFのmRNA低値株では3%(2株/66株)であった。予想通りHGFのmRNA高値株は、ShortpolyA型である頻度が有意に高いことが示された(p=0.04)。次にHGFタンパクの分泌量をELISAで検討したところ、Short polyAであるH69細胞とIM95細胞が、他株と比べて1000倍以上HGFタンパクを分泌することを見出した。一方、Short polyAでもHGF低値の細胞株が存在したことから、9個のHGFプロモーターのSNPを検討した。HGF高値のIM95細胞は、rs3735520がC/Aアレルであったのに対して、他の18株はCアレルであった。rs72525097についてもShort polyA株で頻度が高い傾向を認めた。HGFプロモーターの解析方法としては、自動ゲル解析装置の簡便スクリーニング系およびシークエンスの検証方法を確立した。臨床検体サンプルについては、肺癌30例に対して検討した。自動ゲル解析装置の測定では、そのうち4例にShort polyA型異常が認められた。TAクローニングし、各10クローンのシークエンスを行ったところ、1例はpolyAが14個と著明な短縮を認めた。結論としてHGFpoly A領域の変異は、がん細胞株および臨床検体でHGF発現量を制御する可能性が示唆された。

Research Products

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• [Journal Article] SRFX2 iS a novel chondroitin sulfate proteoglycan that is overexpressed in fastrointestinal cancer (2012)
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• [Journal Article] FGFR2 gene amplification and clinicopathological featuers in gastric cancer. (2012)
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• [Journal Article] Plasma concentrations of angiogenesis-related molecules in patients with pancreatic cancer (2012)
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• [Journal Article] Integrated analysis of whole genome exon array and array-comparative genomic hybridization in gastric and colorectal cancer cells. (2012)
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• [Journal Article] EGRI and FOSB gene expressions in cancer stroma are independent prognostic indicators for epithelial ovarian cancer receiving standard therapy (2012)
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• [Journal Article] Aza-derivatives of resveratrol are potent macrophage migration inhibitory factor inhibitors. (2012)
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• [Journal Article] Expression changes in arrestin β1 and genetic variation in catechol-O-methyltransferase are biomarkers for the response to morphine treatment in cancer patients (2011)
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• [Journal Article] Prospective study evaluating the plasma concentrations of twenty-six cytokines and response to morphine treatment in cancer patients (2011)
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• [Journal Article] What can and cannnot be done using a microarray analysis? Treatment stratification and clinical applications in oncology. (2011)
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• [Journal Article] Serum heparan sulfate concertration is correlated with the failure of epidermal growth factor receptor tyrosine kinase inhibitor treatment in patients with lung adenocarcinoma. (2011)
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• [Journal Article] Differential roles of STAT3 depending on the mechanism of STAT3 activation in gastric cancer cells. (2011)
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• [Journal Article] Switching addictions between HER2 and FGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure. (2011)
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• [Journal Article] Overexpression of cofilin 1 can predict progression-free survival in patients with epithelial ovarian cancer receiving standard therapy. (2011)
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• [Journal Article] Sorafenib inhibits the hepatocyte growth factor-mediated epithelial mesenchymal transition in hepatocellular carcinoma. (2011)
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• [Journal Article] Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy. (2011)
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• [Journal Article] TGF-β induces sustained upregulation of SNAI1 and SNAI2 through Smad and non-Smad pathways in a human corneal epithelial cell line. (2011)
  • Author(s): Aomatsu K
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 52(5) Pages: 2437-43
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• [Journal Article] Antitumor activity of BIBF 1120, a triple angiokinase inhibitor, and use of VEGFR2+pTyr+ peripheral blood leukocytes as a pharmacodynamic biomarker in vivo. (2011)
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• [Journal Article] Enhanced expression of nuclear factor I/B in oxaliplatin-resistant human cancer cell lines (2011)
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  • NAID: 10029290117
  • Peer Reviewed
• [Presentation] Aza-derivatives of resveratrol are inhibitors of macrophage migration inhibitory factor (MIF). (2011)
  • Author(s): Fujita, Y.
  • Organizer: American Association for Cancer Research 102nd Annual Meeting 2011
  • Place of Presentation: Florida
• [Presentation] Somatic mutation profiling to tumor samples using OncoCarta Panel. (2011)
  • Author(s): Furuta, K.
  • Organizer: American Association for Cancer Research 102nd Annual Meeting 2011
  • Place of Presentation: Florida
• [Presentation] Expression levels of EMT-related genes in hepatocellular carcinoma. (2011)
  • Author(s): Nagai, T.
  • Organizer: American Association for Cancer Research 102nd Annual Meeting 2011
  • Place of Presentation: Florida
• [Presentation] Slug-mediated epithelial mesenchymal transition in lugn cancer cells. (2011)
  • Author(s): Tamura, D.
  • Organizer: American Association for Cancer Research 102nd Annual Meeting 2011
  • Place of Presentation: Florida
• [Presentation] Serum concentrations of angiogenesis-related molecules in patients with pancreatic cancer. (2011)
  • Author(s): Kimura, H.
  • Organizer: American Association for Cancer Research 102nd Annual Meeting 2011
  • Place of Presentation: Florida
• [Presentation] FGFR inhibitor regulates CD133 expression in FGFR2-amplified gastric cancer cells. (2011)
  • Author(s): Matsumoto, K.
  • Organizer: American Association for Cancer Research 102nd Annual Meeting 2011
  • Place of Presentation: Florida
• [Presentation] Slug is upregulated during wound healing and downregulates TP63 in corneal epithelial cell. (2011)
  • Author(s): Aomatsu, K.
  • Organizer: ARVO 2011 Vision Genomics
  • Place of Presentation: Florida
• [Presentation] An analysis of serum heparan sulfate concentration and EGFR tyrosine kinase inhibitor treatment in patients with non-small cell lung adenocarcinoma. (2011)
  • Author(s): Nishio, M.
  • Organizer: American Society of Clinical Oncology Annual Meeting 2011
  • Place of Presentation: Chicago
• [Presentation] 血清ヘパラン硫酸濃度とEGRチロシンキナーゼ阻害薬耐性 (2011)
  • Author(s): 松本和子
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市
• [Presentation] 大腸がんにおけるHS6ST2発現とその臨床的特徴 (2011)
  • Author(s): 木村英晴
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市
• [Presentation] 肝細胞癌におけるTJP-1とTwist発現の肝癌切除後の予後への影響 (2011)
  • Author(s): 永井知行
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市
• [Presentation] 非小細胞肺がんにおけるEGFR T790の変異の新規検出法 (2011)
  • Author(s): 藤田至彦
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市
• [Presentation] 胃癌のEMT関連遺伝子発現と化学療法治療予後 (2011)
  • Author(s): 荒尾徳三
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋市
• [Presentation] EMTとバイオマーカー (2011)
  • Author(s): 荒尾徳三
  • Organizer: 第15回日本がん分子標的治療学会
  • Place of Presentation: 東京
• [Patent(Industrial Property Rights)] ソラフェニブの効果予測方法 (2011)
  • Inventor(s): 荒尾徳三、他
  • Industrial Property Rights Holder: 荒尾徳三、他
  • Industrial Property Number: 2011-104275
  • Filing Date: 2011